Gliederung

Objective

Pial arteriovenous malformations (AVMs) and dural arteriovenous malformations (DAVFs) are important CNS manifestations of Osler's disease (M. Osler-Rendu-Weber; HHT, hereditary hemorrhagic teleangiectasia). HHT patients develop vascular dysplasias of the skin, viscera and CNS caused by germline mutations of at least two genes, ENG (HHT type 1) and ALK1 (HHT type 2). Here we propose a role for the ALK1 gene also in the formation of clinically sporadic vascular malformations of the CNS.

Methods

A series of n=266 patients (harboring 112 AVMs, 101 aneurysms, 55 cavernomas, and 3 DAVFs; some patients were diagnosed with more than one malformation) and n=203 controls were investigated for ALK1 sequence variations.

Results

A statistically significant association between the development of AVMs (and possibly DAVFs), but not aneurysms or cavernomas, and a polymorphism located in intron 3 (P=0.0052, OR=2.620, 95% confidence interval 1.260-5.447) was identified. We detected a mutation resulting in the expression of a truncated transcript in exon 4 of the ALK1 gene in 2/218 patients but also 2/191 control subjects. No further mutations were found in the coding sequence (90 patients), and the 5' end and the polyA site (53 AVM patients).

Conclusions

This is the first report linking the ALK1/HHT type 2 gene to the formation of the clinically sporadic variants of vascular malformations of the CNS commonly seen in HHT patients, i.e. AVMs and DAVFs. The ALK1 genotype might significantly influence the risk of an individual to develop AVMs (and DAVFs).